US2017348427A1PendingUtilityA1
Pharmaceutical formulations and methods of use thereof
Est. expiryNov 25, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Elizabeth Bartlett
A61P 35/00C07K 2317/24A61K 39/39591A61K 31/5517A61K 47/12C07K 2317/56A61K 47/186C07K 16/2803C07K 16/2866A61K 47/26C07K 2317/565C07K 16/28A61K 47/183C07D 519/00A61K 47/6849A61K 47/6803A61K 47/68035A61K 9/0019
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Claims
Abstract
This disclosure is directed to antibody-drug conjugates. More specifically, this disclosure is directed to compositions comprising (i) antibody-drug conjugates comprising benzodiazepines, and (ii) a small hydrophobic molecule, methods of treatment using the compositions, and methods of formulating the compositions. Furthermore, this disclosure is directed to methods of reducing reversible self-association in antibodies and in antibody-drug conjugates.
Claims
exact text as granted — not AI-modified1 . A method of formulating an ADC, comprising
(a) reducing reversible self-association in a formulation by
(i) providing an ADC comprising a benzodiazepine in an aqueous solution at a first pH, wherein the ADC exhibits reversible self-association;
(ii) adjusting the pH of the aqueous solution to a second pH, wherein the second pH ranges from about 4.0 to about 4.5, and
wherein the adjustment of the pH from the first pH to the second pH reduces reversible self-association.
2 . The method of claim 1 , wherein the second pH is about 4.2.
3 . The method of claim 1 , wherein the benzodiazepine is selected from the group consisting of D1, D1(a), D2, D2(a), DGN462, DGN462(a), D3, D3(a), D4, D4(a), D5, D5(a), D6, and D6(a).
4 . The method of claim 1 , wherein the ADC is selected from the group consisting of Ab-sSPDB-D1, Ab-sSPDB-D1(a), Ab-D2, Ab-D2(a), Ab-sSPDB-DGN462, Ab-sSPDB-DGN462(a), Ab-D3, Ab-D3(a), Ab-sSPDB-D4, Ab-sSPDB-D4(a), Ab-Cys-D1, Ab-Cys-D1(a), Ab-Ser-D1, Ab-Ser-D1(a), Ab-Cys-DGN462, Ab-Cys-DGN462(a), Ab-Ser-DGN462, Ab-Ser-DGN462(a), Ab-Cys-D5, Ab-Cys-D5(a), Ab-Ser-D6, and Ab-Ser-D6(a).
5 . The method of claim 1 , wherein the reversible self-association is reduced by about 70% to about 80%.
6 . The method of claim 1 , wherein the reversible self-association is reduced by about 80% to about 90%.
7 . The method of claim 1 , wherein the reversible self-association is reduced by about 90% to 100%.
8 . The method of claim 1 , further comprising lyophilizing the aqueous solution, thereby creating a lyophilized composition.
9 . The method of claim 8 , further comprising reconstituting the lyophilized composition.
10 . The method of claim 1 , wherein the ADC comprises an antibody selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3.
11 . The method of claim 1 , wherein the ADC comprises a humanized CD123 antibody.
12 . The method of claim 11 , wherein the humanized CD123 antibody is AbX.
13 . The method of claim 12 , wherein the CD123 antibody is AbX 1 .
14 . The method of claim 13 , wherein AbX 1 comprises the heavy chain variable region CDR sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and the light chain variable region CDR sequences SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.
15 . The method of claim 13 , wherein AbX 1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 7 and a light chain variable region at least about 90% identical to SEQ ID NO: 9.
16 . The method of claim 13 , wherein AbX 1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 11 and a light chain variable region at least about 90% identical to SEQ ID NO: 14.
17 . The method of claim 13 , wherein AbX1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 12 and a light chain variable region at least about 90% identical to SEQ ID NO: 14.
18 . The method of claim 12 , wherein the CD123 antibody is AbX 2 .
19 . The method of claim 18 , wherein AbX 2 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 8 and a light chain variable region at least about 90% identical to SEQ ID NO: 10.
20 . The method of claim 18 , wherein AbX2 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 13 and a light chain variable region at least about 90% identical to SEQ ID NO: 15.
21 . The method of claim 11 , wherein the benzodiazepine is D5 or D5(a).
22 . The method of claim 1 , further comprising adding trehalose dehydrate to the formulation.
23 . A composition comprising:
(a) an ADC comprising a benzodiazepine; and (b) trehalose; wherein the composition has a pH ranges from about 4.0 to about 4.5.
24 . The composition of 23 , further comprising sodium succinate.
25 . The composition of 24 , further comprising sodium bisulfate.
26 . The composition of any one of claims 23 - 25 , further comprising a surfactant.
27 . The composition of any one of claims 23 - 26 , wherein the benzodiazepine is selected from the group consisting of D1, D1(a), D2, D2(a), DGN462, DGN462(a), D3, D3(a), D4, D4(a), D5, D5(a), D6, and D6(a).
28 . The composition of any one of claims 23 - 27 , wherein the ADC is selected from the group consisting of Ab-sSPDB-D1, Ab-sSPDB-D1(a), Ab-D2, Ab-D2(a), Ab-sSPDB-DGN462, Ab-sSPDB-DGN462(a), Ab-D3, Ab-D3(a), Ab-sSPDB-D4, Ab-sSPDB-D4(a), Ab-Cys-D1, Ab-Cys-D1(a), Ab-Ser-D1, Ab-Ser-D1(a), Ab-Cys-DGN462, Ab-Cys-DGN462(a), Ab-Ser-DGN462, Ab-Ser-DGN462(a), Ab-Cys-D5, Ab-Cys-D5(a), Ab-Ser-D6, and Ab-Ser-D6(a).
29 . The composition of any one of claims 23 - 28 , wherein the ADC comprises a humanized CD123 antibody.
30 . The method of claim 29 , wherein the humanized CD123 antibody is AbX.
31 . The method of claim 30 , wherein the CD123 antibody is AbX 1 .
32 . The method of claim 31 , wherein AbX 1 comprises the heavy chain variable region CDR sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and the light chain variable region CDR sequences SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.
33 . The method of claim 31 , wherein AbX 1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 7 and a light chain variable region at least about 90% identical to SEQ ID NO: 9.
34 . The method of claim 31 , wherein AbX 1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 11 and a light chain variable region at least about 90% identical to SEQ ID NO: 14.
35 . The method of claim 31 , wherein AbX 1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 12 and a light chain variable region at least about 90% identical to SEQ ID NO: 14.
36 . The method of claim 30 , wherein the CD123 antibody is AbX 2 .
37 . The method of claim 36 , wherein AbX 2 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 8 and a light chain variable region at least about 90% identical to SEQ ID NO: 10.
38 . The method of claim 36 , wherein AbX 2 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 13 and a light chain variable region at least about 90% identical to SEQ ID NO: 15.
39 . The method of any one of claims 29 - 38 , wherein the benzodiazepine is D5 or D5(a).Join the waitlist — get patent alerts
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